This Program Project grant application was prepared in response PA-01-075 "Integrated Preclinical/Clinical Program for HIV Topical Microbicides". The broad, longterm goals of the proposed studies in this program project grant application are to develop a combination topical microbicide containing a non-nucleoside reverse transcriptase inhibitor. This multi-disciplinary team of investigators proposes to combine UC781, a particularly tight-binding NNRTI with other active agents to create a topical microbicide formulation having activity against several target sites. The Program Project grant is led by Dr. Sharon Hillier at the University of Pittsburgh/Magee-Womens Hospital. In Project 1, Dr. Michael Parniak proposes to conduct in vitro testing of UC781 with other active antiviral components to evaluate whether selection of drug-resistant HIV isolates will occur when a microbicide containing an NNRTI is applied topically. In Project 2, Dr. Phalguni Gupta will test anti-HIV activity and toxicity in a tissue explant model utilizing cervical tissues. In Project 3, Drs. Lisa Rohan and Charles Isaacs will seek to develop combinations of other active agents and excipients to be used with UC781. In Project 4, Dr. Daniel Landers proposes early clinical testing to evaluate the safety and toxicity of UC781, its pharmacokinetics, and transport into the upper genital tract. The Program Project grant is supported by an Administrative and Microbiology Core, both of which are directed by Dr. Sharon Hillier. In addition, this Program Project grant features close collaboration with Biosyn Inc., the company which has licensed UC781 as a topical microbicide and the formation of a Scientific Steering Committee comprised by key personnel from this grant and Biosyn scientists, who will collaborate on the proposed studies. This is a highly interactive and iterative set of studies which are designed to generate new knowledge on model development, selection of HIV resistance and development of innovative formulations which will be broadly applicable in the field of microbicides. In addition, there are studies which are complementary to the traditional drug development pathway for a topical microbicide.